反应详情

To a mixture of zinc dust (50.0 g, 0.765 mol) and 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (50.0 g, 0.206 mol) is added DMF (500 mL). The mixture is allowed to stir for 15 min. To the reaction is then added a mixture of N-(tert-butoxycarbonyl) glycine (43.38 g, 0.247 mol) and HBTU (156.5 g, 0.413 mol) in 5 small portions over a period of 3 hours to control the exothermic reaction. The reaction was stirred for 16 hours. Ethyl acetate (EtOAc) (1300 mL) is then added, and the reaction is filtered through celite. The celite is bed washed with EtOAc (200 mL). The combined EtOAc solutions are washed with water (2×1000 mL) followed by saturated NaCl (500 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The crude residue (103 g) is dissolved in acetic anhydride (150 mL) followed by the addition of zinc dust (13.5 g, 0.206 mol) and triethylamine (25.9 mL, 0.186 mol). The reaction is stirred for 1.15 hours. The solvent (acetic anhydride and triethylamine) is removed under reduced pressure to yield a residue. The residue was dissolved in EtOAc (1000 mL) and washed with water (2×500 mL), 5% sodium bicarbonate (2×500 mL) saturated NaCl (500 mL) and dried over Na2SO4. Concentration of the ethyl acetate solution under reduced pressure yields a yellowish white crude product (103 g) that is purified by crystallization from hexane-ethyl acetate. For crystallization, the crude product is dissolved in refluxing EtOAc (200 mL) and hexane (300 mL) is added. The mixture is allowed to cool to room temperature and stirred for 14 hr. A solid separated out which is collected by filtration and washed with 5% EtOAc in hexane (500 mL). The desired product (38.2 g) is obtained 98% pure with 2% of bis-glycine as a side-product. The 98% pure product (38.2 g) is again crystallized from refluxing EtOAc (165 mL) and hexanes (250 mL). The hot solution is allowed to cool to room temperature and stirred for 15 hr. The white solid obtained is filtered, washed with 5% EtOAc in hexane (400 mL), and dried under high vacuum at 45-50° C. The desired product (34.6 g, 38%) is obtained as a white solid at 99.83% purity based upon HPLC analysis. The 1H NMR is the same as described in Example 5a.

1. additionTo the reaction is then added
2. customthe exothermic reaction
3. stirringThe reaction was stirred for 16 hours
4. filtrationthe reaction is filtered through celite
5. washwashed with EtOAc (200 mL)
6. washThe combined EtOAc solutions are washed with water (2×1000 mL)
7. dry with materialThe organic layer is dried over sodium sulfate
8. concentrationconcentrated under reduced pressure
9. dissolutionThe crude residue (103 g) is dissolved in acetic anhydride (150 mL)
10. stirringThe reaction is stirred for 1.15 hours
11. customThe solvent (acetic anhydride and triethylamine) is removed under reduced pressure
12. customto yield a residue
13. washwashed with water (2×500 mL), 5% sodium bicarbonate (2×500 mL) saturated NaCl (500 mL)
14. dry with materialdried over Na2SO4
15. customConcentration of the ethyl acetate solution under reduced pressure yields a yellowish white crude product (103 g) that
16. customis purified by crystallization from hexane-ethyl acetate
17. customFor crystallization
18. dissolutionthe crude product is dissolved
19. temperaturein refluxing EtOAc (200 mL) and hexane (300 mL)
20. additionis added
21. stirringstirred for 14 hr
22. customA solid separated out which
23. filtrationis collected by filtration
24. washwashed with 5% EtOAc in hexane (500 mL)